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Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema
Pascal Brouillard, … , Kari Alitalo, Miikka Vikkula
Pascal Brouillard, … , Kari Alitalo, Miikka Vikkula
Published May 31, 2024
Citation Information: J Clin Invest. 2024;134(14):e173586. https://doi.org/10.1172/JCI173586.
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Research Article Genetics Vascular biology Article has an altmetric score of 11

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema

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Abstract

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor–like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

Authors

Pascal Brouillard, Aino Murtomäki, Veli-Matti Leppänen, Marko Hyytiäinen, Sandrine Mestre, Lucas Potier, Laurence M. Boon, Nicole Revencu, Arin Greene, Andrey Anisimov, Miia H. Salo, Reetta Hinttala, Lauri Eklund, Isabelle Quéré, Kari Alitalo, Miikka Vikkula

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Figure 6

Embryos homozygous for the Tie1R979W allele display lymphatic defects and altered cell-surface/intracellular TIE1 ratio.

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Embryos homozygous for the Tie1R979W allele display lymphatic defects an...
(A) Macroscopic images of Tie1WT and homozygous Tie1R979W/R979W embryos at E15.5. Scale bars: 2 mm. (B) VEGFR3 staining of dorsal skin from WT and Tie1R979W/R979W embryos at E18.5. Scale bars: 100 μm. (C) Analysis of VEGFR3 polypeptides from the indicated skin lysates at E18.5. (D) Western blot analysis of TIE1 polypeptides from indicated lung lysates at E18.5. (E) Quantification of the proportions of cell-surface 135 kDa and intracellular 125 kDa TIE1 polypeptides relative to total TIE1 from the Western blots in D. The graph “Both bands” is the total TIE1 normalized to HSC70. n = 3 experiments. Statistical analysis by 1-way ANOVA with Tukey’s post hoc test for multiple comparisons. Data shown as mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001. (F) Percentages of the indicated genotypes among pups born from heterozygous TIE1-WT/R979W matings. n = 8 litters (observed WT/WT n = 17, WT/R979W n = 25, R979W/R979W n = 0).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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